title: Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation.
abstract: The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome drives many inflammatory processes and mediates IL-1 family cytokine release. Inflammasome activators typically damage cells and may release lysosomal and mitochondrial products into the cytosol. Macrophages triggered by the NLRP3 inflammasome activator nigericin show reduced mitochondrial function and decreased cellular ATP. Release of mitochondrial reactive oxygen species (ROS) leads to subsequent lysosomal membrane permeabilization (LMP). NLRP3-deficient macrophages show comparable reduced mitochondrial function and ATP loss, but maintain lysosomal acidity, demonstrating that LMP is NLRP3 dependent. A subset of wild-type macrophages undergo subsequent mitochondrial membrane permeabilization and die. Both LMP and mitochondrial membrane permeabilization are inhibited by potassium, scavenging mitochondrial ROS, or NLRP3 deficiency, but are unaffected by cathepsin B or caspase-1 inhibitors. In contrast, IL-1β secretion is ablated by potassium, scavenging mitochondrial ROS, and both cathepsin B and caspase-1 inhibition. These results demonstrate interplay between lysosomes and mitochondria that sustain NLRP3 activation and distinguish cell death from IL-1β release.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Heid
authors.forename: Peter A
authors.initials: PA
authors.lastname: Keyel
authors.forename: Christelle
authors.initials: C
authors.lastname: Kamga
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Russell D
authors.initials: RD
authors.lastname: Salter
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1; D061945:Caspase Inhibitors; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009550:Nigericin; D011188:Potassium; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D061945:Caspase Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D002401:Cathepsin B; D020170:Caspase 1; D009550:Nigericin; D011188:Potassium